As patients live longer and are diagnosed with chronic and often debilitating ailments, the result will be an increase in the need to place protein therapeutics, small-molecule drugs and other medications into targeted areas throughout the body that are currently inaccessible or inconvenient as sites of administration. For example, many vision-threatening diseases, including retinitis pigmentosa, age-related macular degeneration (AMD), diabetic retinopathy, and glaucoma, are incurable and yet difficult to treat with currently available therapies: oral medications have systemic side effects; topical applications may sting and engender poor compliance; injections require a medical visit, can be painful and risk infection; and sustained-release implants must typically be removed after their supply is exhausted (and offer limited ability to change the dose in response to the clinical picture). Another example is cancer, such as breast cancer or meningiomas, where large doses of highly toxic chemotherapies such as rapamycin or irinotecan (CPT-11) are administered to the patient intravenously, resulting in numerous undesired side effects outside the targeted area. Various other target sites (e.g., the eye, brain, ear, kidney, pancreas, etc.) may be accessed with specifically tailored drug pumps fluidically connected to site-appropriate catheters or diffusion membranes.
Implantable drug-delivery systems, which may include a refillable drug reservoir, an actuation mechanism, a cannula and check valve, etc., allow for controlled delivery of pharmaceutical solutions to a specified target. This approach can minimize the surgical incision needed for implantation and avoids future or repeated invasive surgery or procedures. These implantable drug-delivery devices may be fabricated using parylene (a widely-used polymer of p-xylene) and/or other biocompatible material to achieve an active device with full biocompatibility. The pump may be used for delivery of, for example, fluid, cells, biologics, or a suspension of inorganic and/or organic particles into the body of human or animal subjects.
Implantable drug delivery systems may be actuated in many different ways. For example, an electrolytic pump offers several advantages for drug-delivery applications. Their low-temperature, low-voltage and low-power operation makes them well-suited for long-term operation in vivo. Additionally, the gas evolution proceeds even in a pressurized environment (e.g., 200 MPa) and produces oxygen and hydrogen gases that contribute to a volume expansion of about a thousand times greater than that of the electrolyte (e.g., water) used in the reaction, creating an actuation force with a minimal physical footprint. The invention may also be implemented in non-implantable drug-delivery systems such as patch pumps.
A key component of many electrolytic drug-delivery pumps is a force-transducing medium (flexible membrane, piston, deflection diaphragm), which separates the electrolysis chamber and the drug reservoir. The diaphragm temporarily deflects towards the drug reservoir under pressure generated in the electrolysis chamber during drug delivery. Once electrolysis is stopped and gas generation ceases, the gas reconstitutes in the presence of a catalyst (e.g., platinum) and the deflection diaphragm returns to its original conformation. For space efficiency, a deflection diaphragm may be provided with corrugations that increase the diaphragm's expansion volume without increasing its footprint. See, e.g., U.S. Pat. Nos. 8,285,328 and 8,348,897, the entire disclosures of which are hereby incorporated by reference. The higher the aspect ratio of the corrugations (i.e., the taller they are), the greater will be the amount of deflection that the pump will be capable of mechanically.
Typical fabrication schemes for corrugated membranes utilize some form of molding. For example, a polymer formulation may be deposited onto a patterned substrate and cured, following which the finished membrane is removed. Particularly for small-scale corrugated membranes for implantable electrolytic pumps, the substrate may be silicon patterned by, for example, etching. Thus, a photoresist may be applied to a flat silicon wafer in the pattern of the desired corrugations (i.e., one or more concentric circles, ovals, rectangles, etc.); the wafer is then etched (e.g., by deep reactive ion etching, or DRIE) so that the wafer regions underlying the photoresist are unaffected, thereby producing the mold. Such processes may exhibit limitations in terms of height tolerance control and height uniformity, and etching processes are costly.